4-Aminothiazole derivatives

Abstract

Novel 4-aminothiazole derivatives are disclosed. These compounds inhibit cyclin-dependent kinases. These compounds and their pharmaceutically acceptable salts and esters have antiproliferative activity and are useful in the treatment or control of cancer, in particular solid tumors. This invention is also directed to pharmaceutical compositions containing such compounds and to methods of treating or controlling cancer, most particularly the treatment or control of breast, lung, colon and prostate tumors. Also disclosed are intermediates useful in the preparation of these novel 4-aminothiazole derivatives.

1. A compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is 
 
       
         
           
           
               
               
           
         
         R 2  is phenyl which may be substituted by up to four substituents independently selected from halogen or OR 5 ; 
         R 3  is selected from the group
 H, 
 CO 2 R 6 , 
 C(O)R 6 ; 
 SO 2 R 6 , and 
 SO 2 NR 5 R 6 ; 
 
         R 5  and R 6  are each independently selected from the group consisting of:
 H and lower alkyl 
 
       
       or the pharmaceutically acceptable salts or esters thereof. 
     
     
       2. The compound of  claim 1  wherein the phenyl is substituted by fluorine. 
     
     
       3. The compound of  claim 2  wherein the fluorine is on the 3-position of the phenyl ring, said ring being further optionally substituted by fluoro or methoxy. 
     
     
       4. The compound of  claim 2  wherein the phenyl is substituted by OR 5 . 
     
     
       5. The compound of  claim 4  wherein the R 5  is lower alkyl. 
     
     
       6. The compound of  claim 1  selected from the group consisting of:
 4-[4-Amino-5-(3-fluorobenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid tert-butyl ester 
 4-[4-Amino-5-(3-fluoro4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid tert-butyl ester 
 4-[4-Amino-5-(2,3-difluoro-6-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid tert-butyl ester, 
 [4-Amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(3-fluorophenyl)methanone, 
 [4-Amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(3-fluoro-4-methoxyphenyl)methanone, 
 [4-Amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(2,3-difluoro-6-methoxyphenyl)methanone, and 
 1-[4-[4-Amino-5-(3-fluorobenzoyl)thiazol-2-ylamino]piperidin-1-yl]ethanone. 
 
     
     
       7. The compound of  claim 1  selected from the group consisting of:
 [4-Amino-2-(1-methanesulfonylpipeidin-4-ylamino)thiazol-5-yl]-(3-fluoro-phenyl)methanone, 
 1-[4-[4-amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidin-1-yl]ethanone, 
 [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)thiazol-5-yl]-(3-fluoro-4-methoxy-phenyl)methanone, 
 4-[4-Amino-5-(3-fluoro-4-methoxybenzoyl)thiazol-2-ylamino]piperidine-1-sulfonic acid dimethylamide, 
 [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)thiazol-5-yl]-(2,3-difluoro-6-methoxyphenyl)methanone, and 
 [4-Amino-2-(1-methanesulfonyl-piperidin-4-ylamino)thiazol-5-yl]-(2,6-difluorophenyl)methanone. 
 
     
     
       8. The compound of  claim 1  which is [4-Amino-2-(4-methanesulfonylphenylamino)thiazol-5-yl]-(2,3-difluoro-6-methoxyphenyl)methanone. 
     
     
       9. A pharmaceutical composition comprising as an active ingredient an effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
       10. The pharmaceutical composition of  claim 1  which is suitable for parenteral administration. 
     
     
       11. A method for treating a breast or colon tumor comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound according to  claim 1 .